Stem cells help grow human liver tissue 'buds' in mice

Jul. 3, 2013
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Human induced stem cell-derived liver bud. / Takanori Takebe

by Dan Vergano, USA TODAY

by Dan Vergano, USA TODAY

An international stem cell research team reports Wednesday that they have grown functioning human liver tissues in mice.

The human liver "buds" implanted in the mice represent a first experimental step in growing replacement organs from stem cells for transplants, such as liver, pancreas and kidneys, says the research team headed by Japan's Takanori Takebe of the Yokohama City University Graduate School of Medicine. The team relied on a "cocktail" of so-called induced stem cells grown to resemble the nascent liver bud cells used in the experiment.

"The liver bud is formed at the very early stage of development - normally in humans, maybe around five or six weeks," said Takebe, in a Tuesday briefing for reporters. "We basically mimicked this very early transition process of the liver-bud-forming process."

Discovered in 2006, induced stem cells are grown from mature tissues, typically skin cells, into the unspecialized stem cell state that allows for their cultivation into a wide variety of cell types, from brain to blood to liver cells. In the new study reported in the journal Nature, the Japanese team reports they essentially mixed together a trio of induced stem cells that included liver cells to see what would happen.

"They unexpectedly self-organize to form a three-dimensional liver bud - this is a rudimentary liver," Takebe says. Each bud was less than a fifth of an inch across in size and consisted of about 180,000 cells. One novelty of the team's approach was in mixing the cell types to re-create the environment of the early liver, where more often stem cell researchers very carefully segregate cell types from each other in order to grow pure cell colonies of a desired variety.

Implanted into mice, the liver buds released human liver enzymes much more effectively than more massive amounts of liver precursor cells implanted alone in mice. The buds also developed blood vessels and grew to resemble normal liver tissues within about two days of implantation. As a final test, the researchers induced a kind of chemically induced liver failure that resembles the disease in people in 12 of the mice, and they report that implanted liver buds helped the mice survive.

Despite the effort's success, Takebe warned that implants of such tissues in human patients are at least a decade away, after tests of their long-term growth and safety. Concerns linger about cancer risks from stem cells implanted into patients. The liver buds also lacked immune cells that filter toxins from the bloodstream and structural cells that send digestive enzymes into the gut from a real liver.

"The real breakthrough here is that the tissues revascularized, growing new blood vessels, after being implanted," says researcher Alejandro Soto-Gutierrez of the Center for Innovative Pediatric Regenerative Therapies in Pittsburgh. "That's amazing, a very good result."

Soto-Gutierrez credits the inclusion of cells that are precursors to blood vessel walls in the mix of cells that created the liver buds as a reason for their connection to the circulatory systems of the mice.

The team actually implanted the liver buds in the brains of the mice in the study using glass slides. That enabled them to peer through small windows grafted onto the skull of each mouse and monitor the buds' growth. That isn't the plan for human patients, Takebe says. "The most important next step is how to make a huge amount of liver buds for transplant use because you know (the) liver is kind of the largest organ in our body." Finding a way to "mass-produce" human liver buds from induced stem cells for a scaled-up transplant attempt on a human patient, he predicts, will likely take at least five years.